Established estrogen therapies for treatment of hormone-deficiency-induced symptoms and the protective action of estrogens on bones, brains, vessels and other organ systems.
The efficiency of estrogens in the treatment of hormone-deficiency-induced symptoms such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with ovarian dysfunction that is caused in some other way reduces the risk of cardiovascular diseases compared to non-estrogen-treated women (Grady et al., loc. cit.).
In addition, more recent studies confirm a protective action of estrogens against neurodegenerative diseases, such as, e.g., Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl 7): pp. 27-35; Birge 1997, Neurology 48 (Suppl 7): pp.36-41), a protective action with respect to brain functions, such as memory and learning capacity (McEwen et al. 1997, Neurology 48 (Suppl 7): pp. 8-15; Sherwin 1997, Neurology 48 (Suppl 7): pp. 21-26), as well as against hormone-deficiency-induced mood swings (Halbreich 1997, Neurology 48 (Suppl 7): pp. 16-20).
In addition, estrogen replacement therapy has proven effective relative to the reduction of the incidence of colorectal carcinoma (Calle, E. F. et al., 1995, J Natl Cancer Inst 87: 517-523).
In conventional estrogen or hormone replacement therapy (=HRT), natural estrogens, such as estradiol, and conjugated estrogens that consist of equine urine are used either by themselves or in combination with a gestagen. Instead of the natural estrogens, derivatives that are obtained by esterification, such as, e.g., 17β-estradiol-valerate, can also be used.
Because of the stimulating action of the estrogens that are used on the endometrium, which results in an increase of the risk of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986-1992), estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagenic component in the estrogen/gestagen combination avoids hypertrophy of the endometrium, but the occurrence of undesirable intracyclic menstrual bleeding is also linked to the gestagen-containing combination.
Selective estrogens represent a more recent alternative to the estrogen/gestagen combination preparations. Up until now, selective estrogens have been defined as those compounds that have an estrogen-like effect on the brain, bones and vascular system, owing to their antiuterotrophic (i.e., antiestrogenic) partial action, but they do not have a proliferative effect on the endometrium.
A class of substances that partially meet the desired profile of a selective estrogen are the so-called “Selective Estrogen Receptor Modulators” (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9): 531-539). In this case, these are partial agonists of estrogen receptor subtype “ERα.” This substance type is ineffective, however, with respect to the therapy of acute postmenopausal symptoms, such as, e.g., hot flashes. As an example of a SERM, the raloxifene that was recently introduced for the indication of osteoporosis can be mentioned.
Estrogen Receptor Beta (ERβ)
Estrogen receptor β (ERβ) was recently discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). The expression pattern of ERβ differs from that of the ERα (Kuiper et al. (1996), Endocrinology 138: 863-870). ERβ thus predominates over ERα in the rat prostate, while ERα predominates over ERβ in the rat uterus. Areas in which in each case only one of the two ER-subtypes is expressed were identified in the brain (Shugrue et al. (1996), Steroids 61: 678-681; Li et al. (1997), Neuroendocrinology 66:63-67). ERβ is expressed in, i.a., areas that are considered to be important for cognitive processes and “mood” (Shugrue et al. 1997, J Comparative Neurology 388: 507-525).
Molecular targets for ERβ in these brain areas could be the 5HT2a-receptor and the serotonin transporter (G. Fink & B. E. H. Sumner 1996 Nature 383:306; B. E. H. Sumner et al. 1999 Molecular Brain Research, in press). The neurotransmitter serotonin (5-hydroxytryptamine) is involved in the regulation of a considerable number of processes, which can be impaired in menopause. In particular, the effects of menopause on emotion and cognition are connected with the serotoninergic system. Estrogen replacement therapy has proven effective with respect to treatment of these estrogen deficiency-produced symptoms, possibly by modulation of serotonin receptor and transporter expression.
Other organ systems with comparatively higher ERβ-expression encompass the bones (Onoe, Y. et al., 1997, Endocrinology 138: 4509-4512), the vascular system (Register, T. C., Adams, M. R. 1998, J. Steroid Molec Biol 64: 187-191), the urogenital tract (Kuiper, G. J. M. et al. 1997, Endocrinology 138: 863-870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478-483), as well as the testis (Mosselmann, S. et al. 1996 Febs Lett 392 49-53) including the spermatides (Shugrue et al. 1998, Steroids 63: 498-504). The tissue distribution suggests that estrogens regulate organ functions via ERβ. The fact that ERβ is functional in this respect also follows by studies in ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bone mass loss in ERKO-mice, which can be cancelled out by estrogen substitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular media and smooth muscle cell proliferation (Iafrati, M. D. et al. 1997, Nature Medicine 3: 545-548). These protective actions of estradiol are carried out in the ERKO mouse presumably via ERβ.
Observations of βERKO mice provide an indication on a function of ERβ in the prostate and bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677-15682). In addition, female ERKO mice (Lubahn, D. B. et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509-512) as well as female βERKO mice (Krege, J. H., 1998) have fertility disorders. Consequently, the important function of estrogens with respect to maintaining testis and ovary functions as well as fertility is confirmed.
It was possible to achieve a selective estrogen action on specific target organs by subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the ERs. Substances with a preference for ERβ compared to ERα in the in vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). A selective action of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo was not previously shown.
The object of this invention is therefore to prepare compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri and that have in vivo a dissociation with respect to bones rather than the uterus action. The compounds are to have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a higher potency with respect to protection against hormone-deficiency-induced bone mass loss in comparison to uterus-stimulating action in the uterus and/or pronounced action with respect to stimulation of the expression of 5HT2a-receptors and 5HT2a-transporters.
In the broader sense, a structure-action relationship, which allows for access to compounds that have the above-formulated pharmacological profile of better estrogenic action on bones than on the uterus, is to be made available by this invention.
According to the invention, the object above is achieved by the provision of 8β-substituted estra-1,3,5(10)-triene derivatives of general formula I′
in which                R2 means a hydrogen atom, a halogen atom;                    a radical R18— or R18—O—, whereby R18 means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group;            a group R19SO2—O—, in which R19 is an R20R21N group, whereby R20 and R21, independently of one another, mean a hydrogen atom, a C1-C5-alkyl radical, a group C(O)R22, in which R22 represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C3-C7-cycloalkyl radical, an optionally substituted C4-C15-cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or, together with the N-atom, means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;                        R3 means a group R18—O—, R19SO2—O— or —O—C(O)R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2, whereby in addition an aryl, heteroaryl or aralkyl radical can stand for R18;        R6 and R7 each mean a hydrogen atom or together an additional bond;        R6′ and R7′, independently of one another, mean a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2;        R8 means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;        R9 means a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms, or together with R11 means an additional bond;        R11 means a hydrogen atom or together with R9 or together with R12 means an additional bond;        R11′ means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R18′, in which X is an oxygen or sulfur atom, and R18′is an alkyl radical with 1 to 3 carbon atoms;        R12 means a hydrogen atom or together with R11 means an additional bond;        R14 means a hydrogen atom or together with R15 means an additional bond;        R15 means a hydrogen atom or together with R14 or together with R16 means an additional bond;        R16 means a hydrogen atom or together with R15 means an additional bond;        R15′ and R16′, independently of one another, mean a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2;        R17 and R17′ each mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R19SO2—O—;                    a group R18 and a group —C(O)R22 or —O—C(O)R22; a group R18—O— and a group R18—; a group R18—O— and a group —O—C(O)R22, in all above cases with R18, R19 and R22 in each case in the meaning that is indicated under R2; or                        R17 and R17′ together mean a group ═CR23R24, in which R23 and R24, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom;for treatment of estrogen-deficiency-induced diseases and conditions.        
The possible substituents at carbon atoms 6, 7, 9, 11, 15, 16 and 17 can be respectively in α- or β-position.
According to a variant of the invention, preferably compounds of general formula I′ are used,
in which
                R2 means a hydrogen or halogen atom or a hydroxy group;        R3 means a group R18—O—, R19SO2—O— or —O—C(O)R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2, whereby in addition an aryl or aralkyl radical can stand for R18;        R6 and R7 each mean a hydrogen atom;        R6′ means a hydrogen atom, a hydroxy group, a group R22 in the meaning that is indicated under R2;        R7′ means a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2;        R8 means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical;        R9 means a hydrogen atom or together with R11 an additional bond;        R11 means a hydrogen atom or together with R9 an additional bond;        R11′ means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R18′, in which X is a sulfur atom, and R18′, is an alkyl radical with 1 to 3 carbon atoms;        R12, R14, R15 and R16 in each case mean a hydrogen atom;        R16′ means a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22, with R18,                    R19, and R22 in each case in the meaning that is indicated under R2;                        R17 and R17′ in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R19SO2—O—;                    a group R18 and a group —C(O)R22 or —O—C(O)R22; a group R18—O— and a group R18—; a group R18—O— and a group —O—C(O)R22, in all above cases with R18, R19 and R22 in each case in the meaning that is indicated under R2; and                        R17 and R17′ together mean a group ═CR23R24, in which R23 and R24, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.        
Another preferred variant of this invention calls for the use of those compounds of general formula I′,
in which
                R2 means a hydrogen atom or a fluorine atom or a hydroxy group,        R3 means a group R18—O—, R19SO2—O— or —O—C(O)R22, with R18, R19, and R22 in each case in the meaning that is indicated under R2, whereby in addition an aryl or aralkyl radical can stand for R18;        R6 and R7 in each case mean a hydrogen atom;        R6′ means a hydrogen atom or a hydroxy group,        R7′ means a hydrogen atom, a fluorine or chlorine atom, a group R18—O—, R19SO2—O— or —R22, with R18, R19 and R22 in each case in the meaning that is indicated under R2;        R8 means a straight-chain or branched-chain, optionally partially or completely fluorinated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl radical or prop-1-inyl radical;        R9, independently of one another, mean a hydrogen atom or together with R11 an additional bond;        R11′ means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C1-C4-alkyl group, a group —X—R18′, in which X is a sulfur atom and R18′ means a saturated, straight-chain or branched-chain C1-C3-alkyl group, a chloromethyl or chloroethyl group;        R12, R14, R15 and R16 in each case mean a hydrogen atom;        R16′ means a hydrogen atom, a fluorine or chlorine atom or a group R18—O— or —R22, with R18 and R22 in each case in the meaning that is indicated under R2;        R17 and R17′ in each case mean a hydrogen atom; a hydrogen atom and a halogen atom; a hydrogen atom and a benzyloxy group; a hydrogen atom and a group R19SO2—O—;                    a group R18 and a group —C(O)R22 or —O—C(O)R22; a group R18—O— and a group R18—; a group R18—O— and a group —O—C(O)R22, in all above cases with R18, R19 and R22 in each case in the meaning that is indicated under R2; or                        R17 and R17′ together mean a group ═CR23R24, in which R23 and R24, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.        
According to another variant, 8β-substituted estra-1,3,5(10)-triene derivatives of general formula I′ are used
in which
                R6′, R7′, R9, R11, R14, R15, R15′ and R16 in each case stand for a hydrogen atom, or R6′, R7′, R14, R15, R15′ and R16 in each case stand for a hydrogen atom, and R9 and R11 together stand for an additional bond, and all other substituents have the meanings that are indicated in claim 1.        
If the estratriene derivatives of general formula I′ contain additional double bonds in the B-, C- and/or D-ring, then a double bond is preferably in position 9(11), 14(15) or 15(16) or two double bonds are present in positions 9(11) and 14(15) or 15(16).
Another variant of the invention are estratriene derivatives of general formula I′
in which
                R17 and R17′ are a group R18—O— and a group R18—; a group R18— and a group —O—C(O)R22, with R18 and R22 in each case in the meaning that is indicated under R2.        
Of the last-mentioned, in turn those gonatriene derivatives are preferred in which                R17 and R17′ are a hydroxy group and a hydrogen atom, a C1-C4-alkyl group or C2-C4-alkenyl groupand especially preferred are those in which        R17 and R17′ are a hydroxy group and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group.        
Finally, an embodiment exists in that R16′ stands for a group R18—O— or R19SO2—O— with R18 and R19 in each case in the meaning that is indicated under R2; R17 and R17′ each stand for a hydrogen atom and all other substituents can have the meanings that are indicated in general formula I′.
Preferred according to this invention is the use of one or more of the following compounds:                8β-Methyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol        3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol        8β-methyl-estra-1,3,5(10)-triene-3,17β-diol        3-methoxy-8β-methyl-estra-1,3,5(10)-trien-17β-ol        8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol        3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol        8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol        8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol        8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol        3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol        8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol        8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol        8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol        8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol        8β-vinyl-estradiol-3-sulfamate        8β-vinyl-estradiol-3,17-disulfamate        8β-vinyl-estradiol-3-(N-acetyl)-sulfamate        8β-vinyl-estrone-3-sulfamate        8β-vinyl-estron-3-acetate        8β-vinyl-estriol        8β-vinyl-estriol-3-sulfamate        8β-methyl-estrone-3-sulfamate        8β-methyl-estriol        8β-(prop-(Z)-enyl)-estradiol        8β-(n-propyl)-estradiol        8β-ethinyl-estradiol        17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol        17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol        16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol        8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol        8β-methyl-estra-1,3,5(10)-triene-3,17α-diol        8β-vinyl-estradiol-diacetate        8β-methyl-estradiol-diacetate        8β-vinyl-estradiol-17-valerianate        17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol        8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol        8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.        
Other possible configurations of this invention will emerge from the subclaims.
In addition to the above use of the compounds of general formula I′, the invention also relates to the compounds of general formula I itself. These are the compounds of general formula I′ excluding the compounds of general formula I′, in which                R3 is a hydroxy, methoxy or acetyl group, and simultaneously        R2 represents a hydrogen atom,        R6, R6′, R7 and R7′ in each case represent a hydrogen atom;        R8 represents a methyl group,        R9 represents a hydrogen atom or        R9 and R11 together represent an additional bond,        R11′ and R12 in each case represent a hydrogen atom,        R14, R15, R15′, R16 and R16′ in each case represent a hydrogen atom, and        R17 and R17′ stands for a β-hydroxy group and a hydrogen atom; for a β-(2-bromoacetyl)oxy group and a hydrogen atom; for a β-acetyl group and a hydrogen atom; a β-carboxyl group and a hydrogen atom; or        R17 and R17′ together represent an oxygen atom.        
This group of compounds that is disclaimed from the scope of general formula I′ is already known from the following patent and bibliographic references:                FR M2743        Los, Marinus; U.S. Pat. No. 3,806,546        Los, Marinus; U.S. Pat. No. 3,736,345        Los, Marinus; U.S. Pat. No. 3,681,407        Los, Marinus; U.S. Pat. No. 3,501,530        Nagata, Wataru; Itazaki, Hiroshi; JP 45024573        Nagata, Wataru; Itazaki, Hiroshi; Takegawa, Bunichi; JP 45024139        Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004060        Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004059        Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004058        Sakai, Kiyoshi; Amemiya, Shigeo; Chem. Pharm. Bull. (1970), 18(3), 641-3        Yoshioka, Kouichi; Goto, Giichi; Hiraga, Kentaro; Miki, Takuichi; Chem. Pharm. Bull. (1973), 21(11), 2427-31        Tori, K.; Editor(s): James, Vivian H. T.: Horm. Steroids, Proc. Int. Congr., 3rd (1971), Meeting Date 1970, 205-13        Tsukuda, Yoshisuke; Sato, Tomohiro; Shiro, Motoo; Koyama, Hirozo; J. Chem. Soc. B (1969), (4), 336-41        Tsukuda, Yoshiko; Itazaki, Hiroshi; Nagata, Wataru; Sato, Tomohiro; Shiro, Motoo; Koyama, Hirozo; Chem. Ind. (London) (1967), (48), 2047-8        Nakai, Hisayoshi; Koyama, Hirozo; Acta Crystallogr. (1967), 23(4), 674.        
A selective estrogenic action and the use of the known compounds in terms of this invention have not yet been described, however.
In most cases, the already known estratrienes are described as intermediate compounds, as estrogens in the conventional sense or for use in analytical processes.
In the compounds of general formulas I and I′ and in partial structures II and II′ that are described below, a fluorine, chlorine, bromine or iodine atom can always stand for a halogen atom; a fluorine atom is preferred in each case. For the 11β-position, in particular also a chlorine atom can be named as a substituent. In particular, the hydrocarbon radicals, which can be partially or completely halogenated, are fluorinated radicals.
Hydrocarbon radical R18 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl or hexyl radical.
Alkoxy groups OR18 in the compounds of general formulas I and I′ and in partial structures II and II′ that are described below can contain 1 to 6 carbon atoms in each case, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
Representatives of the C1-C5-alkyl radicals R20 and R21 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.
As representatives of straight-chain or branched-chain hydrocarbon radicals R22 with 1 to a maximum of 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.
As perfluorinated alkyl groups, for example, trifluoromethyl, pentafluorethyl and nonafluorobutyl can be mentioned. Representatives of the partially fluorinated alkyl groups are, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.
As a C3-C7-cycloalkyl group, a cyclopropyl, butyl, pentyl, hexyl or heptyl group can be mentioned.
A C4-C15-cycloalkylalkyl radical has 3 to 7 carbon atoms in the cycloalkyl portion; typical representatives are the cycloalkyl groups that are mentioned directly above. The alkyl portion has up to 8 carbon atoms.
As examples of a C4-C15-cycloalkylalkyl radical, the cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl group, etc., can be mentioned.
In terms of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
Aryl always also includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
As substituents for an aryl or heteroaryl radical, for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C1-8-alkyl)- or di(C1-8-alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, can be mentioned.
An aralkyl radical is a radical that contains in the ring up to 14, preferably 6 to 10, C atoms and in the alkyl chain 1 to 8, preferably 1 to 4, C atoms. Thus, as aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2-alkyl, —NO2, —N3, —CN, C1-C20-alkyl, C1-C20-acyl, or C1-C20-acyloxy groups.
The alkyl groups or hydrocarbon radicals can be partially or completely fluorinated or substituted by 1-5 halogen atoms, hydroxy groups or C1-C4-alkoxy groups.
A vinyl or allyl radical is primarily defined with a C2-C5-alkenyl radical.
Other variants of the invention provide one or more, optionally conjugated double bonds in rings B, C and D of the estratriene skeleton, specifically one or more double bonds in positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16. In this case, a double bond in position 7, 8 or in position 11, 12 or two double bonds in positions 6, 7 and 8, 9 are preferred (i.e., the naphthalene system is formed together with the aromatic A-ring).
One or more hydroxyl groups at C atoms 3, 16 and 17 can be esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C1-C14-mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid.
Suitable as such carboxylic acids for esterification are, for example:
Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, and elaidic acid.
Esterification with acetic acid, valeric acid or pivalic acid is preferred.
Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, and mesaconic acid.
Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, and isonicotinic acid.
Esterification with benzoic acid is preferred.
As amino acids, the representatives of these classes of substances that are known sufficiently to one skilled in the art are suitable, for example, alanine, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.
Esterification with β-alanine is preferred.
Preferred according to this invention are the compounds below:                8β-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol        3-methoxy-8β-vinyl-estra-1,3,5(10),9(11)-tetraen-17β-ol        8β-(2′,2′-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β-diol        8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β-ol        8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol        3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17β-ol        8β-(2′,2′-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol        8β-(2′,2′-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β-ol        8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol        8β-ethyl-3-methoxy-estra-1,3,5(10)-trien-17β-ol        8β-vinyl-estradiol-3-sulfamate        8β-vinyl-estradiol-3,17-disulfamate        8β-vinyl-estradiol-3-(N-acetyl)-sulfamate        8β-vinyl-estrone-3-sulfamate        8β-vinyl-estron-3-acetate        8β-vinyl-estriol        8β-vinyl-estriol-3-sulfamate        8β-methyl-estrone-3-sulfamate        8β-methyl-estriol        8β-(prop-(Z)-enyl)-estradiol        8β-(n-propyl)-estradiol        8β-ethinyl-estradiol        17α-ethinyl-8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol        17α-methyl-8β-vinyl-estra-1,3,5,(10)-triene-3,17β-diol        16α-fluoro-8β-methyl-estra-1,3,5(10)-triene-3,17β-diol        8β-vinyl-estra-1,3,5(10)-triene-3,17α-diol        8β-methyl-estra-1,3,5(10)-triene-3,17α-diol        8β-vinyl-estradiol-diacetate        8β-methyl-estradiol-diacetate        8β-vinyl-estradiol-17-valerianate        17β-acetoxy-8β-vinyl-estra-1,3,5(10)-trien-3-ol        8β-vinyl-9β-estra-1,3,5(10)-triene-3,17β-diol        8β-ethyl-9β-estra-1,3,5(10)-triene-3,17β-diol.        
Another aspect of this invention relates to the use of the structural part of Formula II (8β-subst.-estra-1,3,5(10)triene-structural part)
in which R8 represents a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical, as a component of the total structure of compounds that have in vitro dissociation with respect to binding to estrogen receptor preparations of rat prostates and rat uteri, and especially as a component of the total structure of such compounds that have a dissociation in favor of their estrogenic action on bone rather than the uterus.
In addition to the aromatic A-ring, one or more double bonds can be present in the B-, C- and/or D-ring in positions 6(7); 9(11); 11(12); 14(15) and 15(16).
The possible substituents at carbon atoms 6, 7, 11, 15 and 16 can be respectively in α- or β-position.
This invention preferably relates to those structural parts of general formula II′
in which R8 represents a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical.
In the same manner, these structural parts can have one or more double bonds in the B-, C- and/or D-ring in addition to the aromatic A-ring.
The possible substituents at carbon atoms 6, 7, 11, 15, 16 and 17 can in turn be in α- or β-position in each case.
As prodrugs, the esters of the 8β-substituted estratrienes according to the invention have advantages compared to the unesterified active ingredients with respect to their method of administration, their type of action, strength and duration of action.
The sulfamates of 8β-substituted estratrienes according to the invention also have pharmacokinetic and pharmacodynamic advantages. Related effects were already described in other steroid-sulfamates (J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).
In this patent application, steroids on which the 8β-substituted estra-1,3,5(10)triene skeleton is based are described for the treatment of estrogen receptor β-mediated diseases and conditions as selective estrogens, which have in vitro dissociation with respect to binding to estrogen receptor preparations of rat prostates and rat uteri and which have in vivo preferably a dissociation, for example, with respect to bone action rather than uterus action: these substances act in a bone-protective manner over a wide dose range without stimulating the uterus.
In addition, the substances in the male rat can have protective action against orchiectomy-induced bone mass loss, without inhibiting the secretion of pituitary hormones LH and FSH. Their liver action is small in the same dose range.
In addition, the substances exert an estrogen-like action on the vascular system and brain functions. Substances with higher binding to the rat prostate—compared to the rat uterus estrogen receptor—are more potent with respect to increasing the expression of serotonin receptors and transporters, in comparison to their positive effect on the LH release. Processes in whose regulation of neurotransmitters serotonin is involved are therefore advantageously influenced, and the compounds according to the invention exert an advantageous influence especially on mood and cognition.
They can be used as estrogens in the terms described in WO 97/45125 for the production of medications for influencing the level of serotonin or serotonin mRNA in humans.
It was found that the 8β-substituted estra-1,3,5(10)trienes according to the invention are suitable as selective estrogens for the treatment of various conditions and diseases that are characterized by a higher content of estrogen receptor β than estrogen receptor α in the corresponding target tissue or target organ.
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) and the use of the compounds of general formula I′ for the production of pharmaceutical agents, especially for the indications below.
The compounds can be used for the following indications after both oral and parenteral administration.
The novel selective estrogens that are described in this patent can be used as individual components in pharmaceutical preparations or in combination especially with antiestrogens or gestagens. Especially preferred is the combination of selective estrogens with ERα-selective antiestrogens, or with antiestrogens that are peripherally-selectively active, i.e., that do not pass through the blood-brain barriers.
The substances and the pharmaceutical agents that contain them are especially suitable for the treatment of peri- and postmenopausal symptoms, especially hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy, and hormone-deficiency-induced emotional diseases. The substances for hormone substitution and the therapy of hormone-deficiency-induced symptoms in the case of surgical, medicinal or ovarian dysfunction that is caused in some other way are also suitable. Prevention of bone mass loss in postmenopausal women and male-menopausal men, in women who have undergone hysterectomies or in women who were treated with LHRH agonists or LHRH antagonists is also part of this.
The compounds are also suitable for alleviating symptoms of male menopause and female menopause, i.e., for male and female hormone replacement therapy (HRT), specifically both for prevention and for treatment, in addition for treatment of symptoms that are accompanied by a dysmenorrhea as well as for treatment of acne.
In addition, the substances can be used for prophylaxis against hormone-deficiency-induced bone mass loss and osteoporosis, for prevention of cardiovascular diseases, especially vascular diseases such as arteriosclerosis, for inhibition of the proliferation of arterial smooth muscle cells, for treatment of primary pulmonary high blood pressure and for prevention of hormone-deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency-induced impairment of memory and learning capacity.
In addition, the substances can be used for treatment of inflammatory diseases and diseases of the immune system, especially auto-immune diseases, such as, e.g., rheumatoid arthritis.
In addition, the compounds can be used for the treatment of male fertility disorders and prostatic diseases.
The compounds can also be used in combination with the natural vitamin D3 or with calcitriol analogues for bone formation or as supporting therapies to therapies that cause bone mass loss (for example, therapy with glucocorticoids, chemotherapy).
Finally, the compounds of general formula I′ can be used in connection with progesterone receptor antagonists, specifically especially for use in hormone replacement therapy and for treatment of gynecological disorders.
A therapeutic product that contains an estrogen and a pure antiestrogen for simultaneous, sequential or separate use for the selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.
The amount of a compound of general formula I′ that is to be administered varies within a wide range and can cover any effective amount. On the basis of the condition that is to be treated and the type of administration, the amount of the compound that is administered can be 0.01 μg/kg-10 mg/kg of body weight, preferably 0.04 μg/kg-1 mg/kg of body weight, per day.
In humans, this corresponds to a dose of 0.8 μg to 800 mg, preferably 3.2 μg to 80 mg, daily.
According to the invention, a dosage unit contains 1.6 μg to 200 mg of one or more compounds of general formula I′.
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopädie der technischen Chemie [Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue,2, 1961, p. 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf in Württemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. In addition, for percutaneous administration, the active ingredients can be added to, for example, a patch.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that are loaded with active compounds of general formula I′ for local administration, various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with α-, β-, or γ-cyclodextrin or derivatives of the latter (PCT/EP95/02656).
According to the invention, the compounds of general formula I′ can also be encapsulated with liposomes.
Methods
Estrogen Receptor Binding Studies
The binding affinity of the new selective estrogens was tested in competitive experiments with use of 3H-estradiol as a ligand to estrogen receptor preparations of rat prostates and rat uteri. The preparation of prostate cytosol and the estrogen receptor test with prostate cytosol was carried out as described by Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109: 1287-1289).
The preparation of rat uterus cytosol as well as the receptor test with the ER-containing cytosol were basically performed as described by Stack and Gorski, 1985 (Stack, Gorski 1985, Endocrinology 117, 2024-2032) with some modifications as described in Fuhrmann et al. (1995) (Fuhrmann, U. et al. 1995, Contraception 51: 45-52).
The substances that are described in this patent have higher binding affinity to the estrogen receptor of rat prostates than to estrogen receptors of rat uteri. In this case, it is assumed that ERβ predominates in the rat prostates over ERα, and ERα predominates in rat uteri over ERβ. Table 1 shows that the ratio of the binding to prostate and uterus receptors qualitatively coincides with the quotient of relative binding affinity (RBA) to human ERβ and ERα of rats (according to Kuiper et al. (1996), Endocrinology 138: 863-870) (Table 1).
TABLE 1RatRatprost.uterusprost.ER/hERαhERβERβ/ERERuterusEstrogenRBA*RBA*ERα(RBA)(RBA)EREstradiol10010011001001Estrone60370.6320.817α-Estradiol58110.22.41.30.5Estriol14211.542055-Androstenediol61730.1550Genisteine53670.110100Coumestrol9418521.32418*Cited from: Kuiper et al. (1996), Endocrinology 138: 863-870
Table 2 shows the results for the compound 8β-methyl-estra-1,3,5(10)-triene-3,17β-diol (compound D) that is to be used according to the invention as well as for the compounds according to the invention                8β-Vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β-diol (A)        8β-vinyl-estra-1,3,5(10)-triene-3,17β-diol (B)        8β-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,17β-diol (C) and        8β-ethyl-estra-1,3,5(10)-triene-3,17β-diol (E).        
TABLE 2RBARBACompoundRat UterusRat Prostate8β-Vinyl-estra-1831,3,5(10),9(11)-tetraene-3,17β-diol (A)8β-Vinyl-estra-1,3,5(10)-0.763triene-3,17β-diol (B)8β-(2,2-Difluorovinyl)-estra-0.951,3,5(10)-triene-3,17β-diol(C)8β-Methyl-estra-1,3,5(10)-1.367triene-3,17β-diol (D)8β-Ethyl-estra-1,3,5(10)-<0.37triene-3,17β-diol (E)
Compounds A, B, C, D and E show a higher binding affinity to the estrogen receptor of rat prostates than to the estrogen receptor of rat uteri.
In addition, the predictability of the ‘prostate-ER versus the uterus-ER test system’ was confirmed with respect to tissue-selective action by in vivo studies. Substances with a preference for prostate-ER are dissociated in vivo preferably with respect to bone and uterus action in favor of action on bones. In addition, substances with higher binding to the rat prostate—compared to the rat uterus estrogen receptor—are more potent with respect to increasing the expression of serotonin receptors and transporters, in comparison to their positive effect on the LH release.
Bone Studies
Three-month-old female rats are ovariectomized and treated once daily for 28 days with the test compound immediately after the operation. The administration is carried out subcutaneously in arachis oil/ethanol. The animals are sacrificed on the day after the last administration, and tibia as well as uteri are removed. The uteri are weighed, fixed and worked up for histological studies. The determination of bone density is carried out ex vivo on prepared long bones by means of pQCT (quantitative computer tomography). The measurements are made at a distance of 4-6 mm from the ball of the joint of the proximal tibia.
The ovariectomy reduces the density of the trabecular bone in the measured area by about 400 mg of Ca2+/cm3 to about 300 mg of Ca2+/cm3. By treatment with a compound of general formula I according to this invention, the degradation of the bone density is prevented or inhibited. The bone density in the proximal tibia was measured.
The higher binding affinity to the estrogen receptor of rat prostates than to the estrogen receptor of rat uteri is reflected in vivo preferably in considerably lower amounts of the compounds according to the invention, which produce a 50% bone protection, in comparison to the amounts that produce a 50% uterus stimulation, relative to the bone mass loss, which can be measured in ovariectomized, untreated female rats 28 days after the ovariectomy unlike in intact animals that are subjected to sham operations.
The vascular action of the estrogens according to the invention is determined in the model of the ApoE-knockout mouse, as described by R. Elhage et al., 1997, as well as in the model of the balloon-catheter-induced vascular damage (restenosis model) (Elhage, R. et al. 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17: 2679-2684).
To detect the action of estrogens on the brain function, the oxytocin-, oxytocin receptor- or vasopressin-mRNA expression is used as a surrogate parameter (Hrabovszky, E. et al. 1998, Endocrinology 1339: 2600-2604). Ovariectomized rats are treated for 7 days with the test substance or vehicle (administration: subcutaneous or oral, six times daily). On day 7 after the first administration, the animals are decapitated, the uterus weight is determined, and the oxytocin-, oxytocin receptor-, or vasopressin-mRNA level is studied by means of in situ hybridization in suitable brain sections. The ED50 values are determined with respect to stimulation of uterus growth and induction of the oxytocin receptor mRNA.
Another possibility to demonstrate in vivo the dissociated estrogen action of the substances according to the invention consists in the fact that after a one-time administration of the substances in rats, effects on the expression of 5HT2a-receptor and serotonin transporter protein and mRNA levels in ERβ-rich brain areas can be measured. Compared to the effect on the serotonin receptor and transporter expression, the effect on the LH-secretion is measured. Substances with higher binding to the rat prostate—compared to the rat uterus estrogen receptor—are more potent with respect to increasing the expression of serotonin receptors and transporters, in comparison to their positive effect on the LH release. The density of serotonin receptors and transporters is determined in brain sections using radioactive ligands, and the corresponding mRNA is determined using in situ hybridization. The method is described in the literature: G. Fink & B. E. H. Sumner 1996 Nature 383: 306; B. E. H. Sumner et al. 1999 Molecular Brain Research, in press.
In accordance with their stronger binding to the rat prostate rather than the rat uterus estrogen receptor, substances A, B, C, D and E according to the invention result in an increased expression of the serotonin receptor and transporter.
Production of the Compounds According to the Invention
The compounds of general formula I (or I′) according to the invention are produced as described in the examples. Additional compounds of general formula I′ can be obtained by an analogous procedure using reagents that are homologous to the reagents that are described in the examples.
Etherification and/or esterification of free hydroxy groups is carried out according to methods that are common to one skilled in the art.
The compounds according to the invention can be present in carbon atoms 6, 7, 11, 15, 16 and 17 as α,β-stereoisomers. In the production of compounds according to the described processes, the compounds in most cases accumulate as mixtures of the corresponding α,β-isomers. The mixtures can be separated by, for example, chromatographic processes.
According to general formula I, possible substituents can already be present in final form or in the form of a precursor even in the starting product, a substituted estrone already corresponding to the desired end product.
The introduction of a substituent or reactive precursor on carbon atom 7 by nucleophilic addition of the substituent or precursor on a 6-vinylsulfone thus is possible (DE 42 18 743 A1). In this case, 7α- and 7β-substituted compounds, which can be separated by, for example, chromatographic processes, are obtained in different proportions, based on the reactants and the selected reaction conditions.
17-Substituents are also introduced according to known processes by nucleophilic addition of the desired substituent or a reactive precursor thereof and are optionally further built up.
The 8β-substituted estratriene-carboxylic acid esters according to the invention are produced from the corresponding hydroxy steroids analogously to processes that are also known (see, e.g., Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwendungen [Pharmaceutical Active Ingredients, Syntheses, Patents, Applications]; A. Kleemann, J. Engel', Georg Thieme Verlag Stuttgart 1978, Arzneimittel, Fortschritte [Pharmaceutical Agents, Improvements] 1972 to 1985; A. Kleemann, E. Lindner, J. Engel (Editors), VCH 1987, pp. 773-814).
The estratriene-sulfamates according to the invention are available in a way that is known in the art from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).
Subsequent acylation of the sulfamide group results in the (N-acyl)sulfamates according to the invention, for which pharmacokinetic advantages were already detected in the case of the absence of an 8-substituent (cf. DE 195 40 233 A1).
The regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides is carried out according to partial protection of those hydroxyl groups that are to remain unesterified. Silyl ethers have turned out to be protective groups with selective reactivity that is suitable for this purpose, since these silyl ethers are stable under the conditions of sulfamate formation, and the sulfamate group remains intact when the silyl ethers are cleaved again for regeneration of the residual hydroxyl group(s) still contained in the molecule (Steroids 61, 710-717 (1996)). The production of the sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible in that the starting material is suitable hydroxy-steroid ketones. First, depending on the goal, one or more hydroxyl groups that are present are subjected to sulfamoylation. Then, the sulfamate groups optionally can be converted with a desired acyl chloride in the presence of a base into the (N-acyl)sulfamates in question. The now present oxosulfamates or oxo-(N-acyl)sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717 (1996)). Sodium borohydride and the borane-dimethyl sulfide complex are suitable as suitable reducing agents.
Functionalizations at carbon atom 2 are possible, for example, by electrophilic substitution after prior deprotonation of the 2-position of the corresponding 3-(2-tetrahydropyranyl)- or 3-methyl ether with a lithium base (e.g., methyllithium, butyllithium). Thus, for example, a fluorine atom can be introduced by reaction of the C—H-activated substrate with a fluorinating reagent such as N-fluoromethane sulfonimide (WO 94/24098).
The introduction of variable substituents in rings B, C and D of the estratriene skeleton can basically be carried out according to the chemical teaching that is known to one skilled in the art, with which the corresponding estratriene derivatives that are not substituted in 8-position are produced (see, i.a.: Steroide [Steroids], L. F. Fieser, M. Fieser, Verlag Chemie, Weinheim/Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, J. A. Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistry of Steroids, F. J. Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990). This relates to, for example, the introduction of substituents, such as hydroxyl or alkyloxy groups, alkyl, alkenyl or alkinyl groups or halogen, especially fluorine.
Substituents according to general formula I can also be introduced in the stage of estratrienes that are already substituted in 8-position, however. This can be useful or necessary especially in the case of multiple substitutions of the desired final compound.
The examples below are used for a more detailed explanation of the invention.
The general synthesis routes for these examples are shown in figures 1 to 3.
As starting material for such syntheses, 11-keto-estratetraene derivatives of type 1 or 2 (U.S. Pat. No. 3,491,089, Tetrahedron Letters, 1967, 37, 3603), which are substituted stereoselectively in 8β-position in the reaction with diethylaluminum cyanide, are used. By subsequent reduction of the carbonyl function at C(11) and elimination of the hydroxyl group that is produced, 8β-substituted estra-1,3,5(10),9(11)-tetraenes, which in turn can be converted into 8β-aldehydes, are obtained. A functionalization, e.g., by Wittig reactions with subsequent removal of protective groups, results in the 8β-steroids according to the invention.
The 11-oxidized estradiol derivatives that are first obtained in this sequence can be further reacted to many substitution patterns on the steroid like the double bond C(9)-C(11) according to methods that are known to one skilled in the art. For example, an 11α-hydroxy group can be converted into an 11β-fluorine atom according to the process that is described by Vorbrüggen et al.
For the production of the derivatives of 8β-substituted estra-1,3,5(10)-triene-3,16ξ-diols according to the invention without 17-substituents, mainly the following synthesis strategy is used. In this connection, the 8β-carbonyl function is protected as an acetal. After subsequent oxidation, the 17-ketosteroid can be converted into a sulfonylhydrazone, in the simplest case by reaction with phenylsulfonyl hydrazide. By a degradation reaction, the formation of the C(16)-C(17) olefin is carried out (Z. Chem. 1970, 10, 221-2; Liebigs Ann. Chem. 1981, 1973-81), on which hypobromide is stored in a regio/stereocontrolled way. Reductive dehalogenation and removal of the acetal protective group at 8β opens the way for transformations to the compounds according to the invention. The 16β-alcohols that can be obtained according to this method can be converted into the 16α-epimer by known methods (Synthesis 1980, 1).
Another variant for the introduction of the hydroxyl group at C-atom 16 consists in the hydroboration of the 16(17)-double bond with sterically exacting boranes. Of this reaction, it is known that it results in 16-oxidized products (Indian J. Chem. 1971, 9, 287-8). The reaction of the estra-1,3,5(10),16-tetraene 17 with 9-borabicyclo[3.3.1]nonane after the oxidation with alkaline hydrogen peroxide consequently produces 16α-hydroxyestratrienes. The epimeric 16β-hydroxy steroids are formed to a lesser extent in this reaction. Further transformations on the 8β-substituent then result in the compounds of general formula I according to the invention.
Characteristic, but not limiting synthesis processes, which are useful for providing representative substitution patterns on the estrone skeleton, also in combination with several substituents, are found in, for example: C(1) J. Chem. Soc. (C) 1968, 2915; C(7) Steroids 54, 1989, 71; C(8α) Tetrahedron Letters 1991, 743; C(8β) Tetrahedron Letters 1964, 1763; J. Org. Chem. 1970, 35, 468; C(11) J. Steroid Biochem. 31, 1988, 549; Tetrahedron 33, 1977, 609 and J. Org. Chem. 60, 1995, 5316; C(9) DE-OS 2035879; J. Chem. Soc. Perk. 1 1973, 2095; C(15) J. Chem. Soc. Perk. 1 1996, 1269.); C(13α) Mendeleev Commun. 1994, 187; C(14β) Z. Chem. 23, 1983, 410.
In the examples and in the figures, the following abbreviations apply:                THF=tetrahydrofuran; THP=tetrahydropyran-2-yl; DHP=dihydropyran; DMSO=dimethyl sulfoxide; MTBE=methyl-tert-butyl ether; DIBAH=diisobutyl-aluminum hydride; LTBAH=lithium-tri-tert.-butoxyaluminum hydride.        